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Transcript 36x48 Horizontal Poster - CTN Dissemination Library

Use of an Adaptive Treatment Research Design in a CTN study of prescription opioid dependence treatment
RD
1,2
Weiss ,
JS
2,3
Potter ,
M
4
Byrne ,
C
4
Sullivan ,
W
5
Ling
1. McLean Hospital, Belmont, MA, USA
2. Department of Psychiatry, Harvard Medical School, Boston, MA, USA
3. University of Texas Health Science Center, San Antonio, TX, USA
4. West Virginia University School of Medicine, Morgantown, WV, USA
5. UCLA School of Medicine, Los Angeles, CA, USA
Aims
Abstract
Aims: The NIDA Clinical Trials is conducting the Prescription
Opioid Addiction Treatment Study (POATS) – a multi-site trial
examining different lengths and intensities of buprenorphine
and drug counseling for subjects with prescription opioid
dependence. The primary aim is to determine whether adding
counseling to buprenorphine plus medical management
improves outcome in this population during Phase 1, an initial
4-week taper, and Phase 2, a subsequent 12-week stabilization
treatment for those who relapsed during or soon after Phase 1.
Methods: This study employs an adaptive treatment research
design (ATRD). Subjects with poor outcomes in Phase 1 enter
Phase 2, at which time they are randomized to a new
treatment.
Results: This study has completed recruitment: Phase 1
(N = 653); Phase 2 (N = 360). Conducting POATS has revealed
some advantages and challenges to using an ATRD.
Advantages include being able to approximate real-world
clinical practice and simultaneously answer multiple research
questions. Challenges include 1) masking the eligibility criteria
for Phase 2 from subjects; 2) developing a clinical threshold for
when to respond to subjects who respond poorly to Phase 1;
and 3) powering the study based on uncertain estimates for
Phase 2 enrollment.
Conclusions: ATRD, applied to the POATS study, presents an
opportunity to evaluate a treatment strategy rather than a
discrete intervention. This research design has advantages and
challenges that researchers need to consider in both the design
and implementation stages of a clinical trial.
The NIDA Clinical Trials is conducting the Prescription
Opioid Addiction Treatment Study (POATS) – a multisite trial examining different lengths and intensities of
buprenorphine and drug counseling for subjects with
prescription opioid dependence. The primary study aim
is to determine whether adding individual drug
counseling (e.g., Enhanced Medical Management
(EMM)) to buprenorphine plus Standard Medical
Management (SMM) improves outcome in this
population during Phase 1, an initial 4-week taper, and
Phase 2, a subsequent 12-week stabilization treatment
for those who relapsed during or soon after Phase 1.
(Figure 1)
Methods
POATS employs an adaptive treatment research design
(ATRD1); in an ATRD, subjects receive an initial
treatment (pre-specified or randomly assigned), with a
plan to evaluate treatment response and potentially
make clinical adjustments when a pre-specified time
point or clinical status (e.g., remission or relapse) is
reached. ATRD has been used elsewhere in psychiatry2
and in general medicine3, but has been used infrequently
in drug abuse studies. In POATS, subjects with poor
outcomes in Phase 1 (Table 1) enter Phase 2, at which
time they are randomized to a new treatment. The
advantages and known challenges to employing an
ATRD were considered in the design of POATS.
Anecdotal reports of unforeseen challenges were
collected from study sites during the course of the trial.
Figure 1: Study Design
Results
Recruitment is complete for POATS. 653 subjects were
randomized to Phase 1. 360 subjects were randomized
to Phase 2. Conducting POATS revealed some
advantages and challenges of an ATRD in the context of
a drug abuse study.
Advantages include 1) the ecological validity associated
with a study designed to approximate real-world clinical
practice (i.e., start with a relatively non-intensive
approach, then instituting more intensive treatment if
the first treatment fails), and 2) the ability to answer
multiple research questions in one study4.
Challenges include 1) masking from subjects the
eligibility criteria that trigger randomization into
Phase 2; 2) establishing a threshold for deciding when it
is clinically necessary to rescue subjects who respond
poorly to the Phase 1 treatment; and 3) powering a
study for Phase 2 when there is uncertainty about how
many participants from the original population will be
eligible for and enter Phase 2. We managed the first
challenge by emphasizing the importance of not
disclosing Phase 1 failure criteria during initial training
and booster sessions with study staff. The second
challenge was addressed after extensive consultation and
feedback from clinical experts in the field. To address
the third challenge, conservative assumptions were
made a priori that about 50% of subjects randomized to
Phase 1 will meet treatment failure criteria and agree to
be randomized in Phase 2.
Table 1: Phase 1 Treatment
Failure Criteria
 Injection drug use
 Participation in other formal substance
abuse treatment
 Beginning on Study Day 15:
 Opioid use > 4 days in the last 28
days
 Opioid-positive urine drug screens
for 2 consecutive visits
 >1 missing urine sample
Conclusions
POATS presents a unique opportunity to evaluate a
treatment strategy for prescription opioid dependence,
rather than a discrete treatment intervention.
Researchers need to weigh the advantages and
challenges when considering an ATRD applied to drug
abuse studies.
Bibliography
1.Tunis, S.R., D.B. Stryer, and C.M. Clancy,
Practical clinical trials: increasing the value of
clinical research for decision making in clinical
and health policy. JAMA, 2003. 290(12): p. 162432.
2.Rush, A.J., et al., Sequenced treatment
alternatives to relieve depression (STAR*D):
rationale and design. Control Clin Trials, 2004.
25(1): p. 119-42.
3.Materson, B.J., et al., Response to a second single
antihypertensive agent used as monotherapy for
hypertension after failure of the initial drug.
Department of Veterans Affairs Cooperative
Study Group on Antihypertensive Agents. Arch
Intern Med, 1995. 155(16): p. 1757-62.
4.Brown, C.H., et al., Adaptive designs for
randomized trials in public health. Annu Rev
Public Health, 2009. 30: p. 1-25.
Support
NIDA Grants DA15831, DA022288,
DA022297, DA013045, DA020036
Conflict of Interest
Dr. Weiss has consulted to Titan
Pharmaceuticals; Dr. Sullivan has spoken
for Pfizer and Reckitt-Benckiser.
Contact Information
Roger D. Weiss, M.D.
McLean Hospital
Division of Alcohol and Drug Abuse
115 Mill Street
Belmont, MA 02478
Email: [email protected]
Phone: 617-855-2242